Augmentation of GABAA receptor function by chronic exposure to GABA-neutral and GABA-negative benzodiazepine ligands in cultured cortical neurons. 1990

L G Miller, and J Heller, and M Lumpkin, and C L Weill, and D J Greenblatt, and R I Shader
Department of Psychiatry, Tufts University School of Medicine, Boston, MA.

Chronic benzodiazepine agonist administration may lead to decreases in gamma-aminobutyric acidA (GABAA) receptor binding and function, but little information is available concerning chronic GABA-neutral or GABA-negative benzodiazepine exposure. We evaluated effects of chronic exposure to flumazenil (Ro15-1788) and FG 7142 (N-methyl-beta-carboline-3-carboxamide) on GABA-dependent chloride uptake in chick cerebral cortical neurons in primary culture. Acute flumazenil treatment (1 microM) had no effect on chloride uptake, but uptake was increased after 2 days of exposure. Similar increases were observed after 4 and 10 days. Flumazenil, 0.1 microM, had no effect after 10 days, and a 10 microM concentration had a similar effect as the 1 microM concentration. Acute FG 7142 (1 microM) decreased chloride uptake, but uptake was increased markedly after 2, 4, and 10 days of treatment. No effect was observed after treatment for 10 days with 0.1 microM, but a 10 microM concentration showed similar enhancement to the 1 microM concentration. Concurrent treatment with 0.3 microM flumazenil which did not affect chloride uptake and 1 microM FG 7142 for 10 days substantially attenuated the effects of FG 7142, suggesting that FG 7142 effects are mediated at the benzodiazepine site. Benzodiazepine receptor binding was increased in cultures treated for 10 days with 1 microM flumazenil or FG 7142, with an increase in receptor number in both cases but no change in apparent affinity. Neither flumazenil nor FG 7142 (1 microM for 10 days) altered GABA-independent chloride uptake, total cellular protein, protein synthesis or degradation, or neuronal survival. These results indicate that both chronic GABA-neutral and GABA-negative benzodiazepine exposures in cultured cortical neurons lead to increases in GABA-dependent chloride uptake and benzodiazepine binding. Effects of GABA-negative benzodiazepine exposure appear to be greater than those observed with GABA-neutral benzodiazepine exposure.

UI MeSH Term Description Entries
D009118 Muscimol A neurotoxic isoxazole isolated from species of AMANITA. It is obtained by decarboxylation of IBOTENIC ACID. Muscimol is a potent agonist of GABA-A RECEPTORS and is used mainly as an experimental tool in animal and tissue studies. Agarin,Pantherine
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D010042 Ouabain A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like DIGITALIS. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-EXCHANGING ATPASE. Acocantherin,G-Strophanthin,Acolongifloroside K,G Strophanthin
D011963 Receptors, GABA-A Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop. Benzodiazepine-Gaba Receptors,GABA-A Receptors,Receptors, Benzodiazepine,Receptors, Benzodiazepine-GABA,Receptors, Diazepam,Receptors, GABA-Benzodiazepine,Receptors, Muscimol,Benzodiazepine Receptor,Benzodiazepine Receptors,Benzodiazepine-GABA Receptor,Diazepam Receptor,Diazepam Receptors,GABA(A) Receptor,GABA-A Receptor,GABA-A Receptor alpha Subunit,GABA-A Receptor beta Subunit,GABA-A Receptor delta Subunit,GABA-A Receptor epsilon Subunit,GABA-A Receptor gamma Subunit,GABA-A Receptor rho Subunit,GABA-Benzodiazepine Receptor,GABA-Benzodiazepine Receptors,Muscimol Receptor,Muscimol Receptors,delta Subunit, GABA-A Receptor,epsilon Subunit, GABA-A Receptor,gamma-Aminobutyric Acid Subtype A Receptors,Benzodiazepine GABA Receptor,Benzodiazepine Gaba Receptors,GABA A Receptor,GABA A Receptor alpha Subunit,GABA A Receptor beta Subunit,GABA A Receptor delta Subunit,GABA A Receptor epsilon Subunit,GABA A Receptor gamma Subunit,GABA A Receptor rho Subunit,GABA A Receptors,GABA Benzodiazepine Receptor,GABA Benzodiazepine Receptors,Receptor, Benzodiazepine,Receptor, Benzodiazepine-GABA,Receptor, Diazepam,Receptor, GABA-A,Receptor, GABA-Benzodiazepine,Receptor, Muscimol,Receptors, Benzodiazepine GABA,Receptors, GABA A,Receptors, GABA Benzodiazepine,delta Subunit, GABA A Receptor,epsilon Subunit, GABA A Receptor,gamma Aminobutyric Acid Subtype A Receptors
D002243 Carbolines A group of pyrido-indole compounds. Included are any points of fusion of pyridine with the five-membered ring of indole and any derivatives of these compounds. These are similar to CARBAZOLES which are benzo-indoles. Carboline,Pyrido(4,3-b)Indole,Beta-Carbolines,Pyrido(4,3-b)Indoles,Beta Carbolines
D002642 Chick Embryo The developmental entity of a fertilized chicken egg (ZYGOTE). The developmental process begins about 24 h before the egg is laid at the BLASTODISC, a small whitish spot on the surface of the EGG YOLK. After 21 days of incubation, the embryo is fully developed before hatching. Embryo, Chick,Chick Embryos,Embryos, Chick
D002712 Chlorides Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Chloride,Chloride Ion Level,Ion Level, Chloride,Level, Chloride Ion
D005442 Flumazenil A potent benzodiazepine receptor antagonist. Since it reverses the sedative and other actions of benzodiazepines, it has been suggested as an antidote to benzodiazepine overdoses. Flumazepil,Anexate,Lanexat,Ro 15-1788,Romazicon,Ro 15 1788,Ro 151788
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001067 Appetite Depressants Agents that are used to suppress appetite. Anorectic,Anorectic Agent,Anorectics,Anorexic Drug,Anorexigenic Drug,Appetite Depressant,Appetite Suppressant,Appetite Suppressants,Appetite-Depressing Drug,Appetite-Suppressant Drug,Anorectic Agents,Anorexic Drugs,Anorexigenic Drugs,Appetite-Depressing Drugs,Appetite-Suppressant Drugs,Agent, Anorectic,Agents, Anorectic,Appetite Depressing Drug,Appetite Depressing Drugs,Appetite Suppressant Drug,Appetite Suppressant Drugs,Depressant, Appetite,Depressants, Appetite,Drug, Anorexic,Drug, Anorexigenic,Drug, Appetite-Depressing,Drug, Appetite-Suppressant,Drugs, Anorexic,Drugs, Anorexigenic,Drugs, Appetite-Depressing,Drugs, Appetite-Suppressant,Suppressant, Appetite,Suppressants, Appetite

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